1. Field of the Invention
This invention relates to a combination of aspirin, certain B vitamins and folic acid to prevent and or decrease cardiovascular diseases, heart attack and stroke, to a stable daily administration pack for such combination to facilitate the patient's compliance with recommendation or instruction to take such combination, and to the method of treating and preventing cardiovascular diseases with the help of such combination.
Cardiovascular disease ranks as the leading cause of mortality and morbidity in the United States today. This year, it is estimated that 1.5 million people will have a heart attack and that one third of those will die as a result of CAD.
The American College of Cardiology recently identified other abnormalities as factors for which intervention is likely to lower stroke and heart disease risk. Elevated total blood cholesterol is frequently considered a risk factor for coronary artery disease (CAD), but it is important to note that in the Framingham study 80% of CAD patients had the same total cholesterol as those who did not develop CAD.
2. Definition of Certain Terms
Throughout the specification and associated claims, terms listed below shall be read as having the meaning here stated:
CAD Coronary artery disease LDL Low density lipoprotein IDL Intermediate density lipoprotein MI Myocardial infarction PVD Peripheral vascular disease
3. State of the Prior Art
Heredity remains the number one risk factor in heart disease; 77% of people in the United States with heart disease have inherited metabolic traits contributing to their atherosclerosis. Lp (a) is a LDL with protein (a) attached, and elevated level of Lp (a) is an inherited trait present in approximately 33% of heart disease patients. Elevated levels of Lp (a) increase the risk of heart disease by 300%, yet Lp (a) is not detected in traditional lipid profile tests. A powerful predictor of heart attacks in young men and of vein graft blockage following bypass surgery, elevated levels of Lp (a) also increase the danger of other risk factors. High Lp (a) can be treated with niacin. Niacin (nicotinic acid) or niacinamide is a member of the Vitamin B-complex group (vitamin B3). Buoyant LDLs are the lighter, larger LDLs found primarily in LDL pattern A people. Dense LDLs are the heavier, smaller LDLs found primarily in LDL pattern B people. LDL density change is the strongest predictor of percent change in coronary artery stenosis.
There is substantial evidence that reduction in small LDL is more important than reduction in LDL-cholesterol in achieving improvements. Following treatment with niacin, small LDL subclass patterns significantly improve with a larger LDL diameter. This is also associated with improvement in other abnormalities such as elevated IDL, elevated LP (a) and enhanced postprandial lipemia.
The chief drawback of using niacin in the treatment of hyperlipidemia is facial and truncal flushing, which occurs in nearly all users shortly after ingestion of a tablet with as small a dosage as 75 mg of niacin. It appears that niacin induces flushing by increasing the formation and/or release of some prostaglandin, which in turn increases the production of cyclic amp. Aspirin is a prostaglandin inhibitor and reduces the incidence and severity of flushing. Aspirin therapy has been well established as a platelet aggregate inhibitor and is now widely used. It has been shown to be the strongest therapeutic known to reduce the risk of a stroke, a first heart attack in healthy individuals, and subsequent heart attacks or strokes.
Recent evidence suggests that elevated blood levels of homocystine, which is derived from the amino acid methionine, is linked to heart disease. Homocystine is a sulfur-containing amino acid formed during the metabolism of methionine.
Homocystine increases the formation of highly atherogenic oxycholesterols, increases lipid peroxidation, and increases the oxidation of LDL in vitro. These observations suggest a potential role for antioxidant therapy in ameliorating homocystine-dependent oxidative vascular injury.
Patients with mild hyperhomocystinemia have none of the clinical signs of severe hyperhomocystinemia and are typically asymptomatic until the third or fourth decade of life when premature CAD develops, as well as recurrent arterial and venous thrombosis. How the body metabolizes, or breaks down, homocystine can be determined genetically. People who inherit a defective gene for homocystine metabolism tend to have elevated homocystine blood levels--a trait found in 20-30% of patients with atherosclerosis.
Three B-vitamins, folate and vitamins B6 and B12, play essential roles as cofactors in homocystine metabolism. Elevated plasma homocystine (even when caused by genetic variants) can usually be normalized by moderate vitamin supplementation. Folic acid alone, folic acid combined with B12 and B6, and vitamins B6 and B12 have all been shown to reduce homocystine concentrations. Normalization of the plasma homocystine concentration usually occurs within four to six weeks after the initiation of therapy, but may occur in as little as two weeks. Interestingly, the reduction in mortality from cardiovascular causes since 1960 has been correlated with the increase in vitamin B6 supplementation in the food supply.
A retrospective analysis of dietary vitamin C and E intake was done in the CLAS trial (n=156) and indicated an association between supplementary vitamin E intake and angiographically demonstrated reduction in coronary artery lesion progression.
The Cambridge Heart Attack and Antioxidant Study studied 2002 CAD patients, randomized to 800 IU vitamin E per day or placebo for 1.5 years, and revealed a significant reduction in non-fatal MI in the vitamin E group.
In recent years, however, awareness has grown that any medication regimen is only as good as the patient's compliance with it, that is that prescribed medications are actually taken at the times and in the amounts prescribed. The problem, and some ingenious but labor intensive and costly attempts to solve it, is well summarized in an article "The Other Drug Problem: Forgetting to Take Them" by science writer Abigail Zuber (New York Times, Jun. 2, 1998), which is here incorporated by reference in its entirety and from which the following is excerpted. "Study after study over the last 20 years has shown that misuse of prescription drugs is a worldwide epidemic every bit as dangerous and costly as an actual medical illness. It was tagged `America's other drug problem` in the early 1990's when researchers consistently found it responsible for 10 to 25 percent of hospital and nursing home admissions studied. In 1984, the National Pharmaceutical Council, an association of pharmaceutical companies, estimated that misuse of prescription drugs had caused 125,000 deaths a year from heart disease alone. In 1993 the same organization calculated that not taking medicines correctly was draining upwards of $100 billion a year from the nation's economy in direct and indirect costs.
And with increased cost consciousness has come a new appreciation of the problem of `noncompliance,` as medicine has labeled the phenomenon of skipping some doses, doubling up on others, forgetting to refill at the end of the month or taking a few of a family member's antibiotics on the chance they will work better than the ones prescribed.
Interest has been sharpened by new studies clearly demonstrating that disorders like elevated blood cholesterol or asthma respond far better when patients take medications as prescribed. And the flip side of the equation has been vividly illustrated by the medications for tuberculosis and AIDS: they may actually damage a patient's health when taken improperly, by inducing drug-resistant disease that may be passed on to others and cannot be treated at all. In fact, improving medication-taking behavior may be one of the few arenas in health care today where widely disparate interest groups--including medical researchers, patient advocates, drug companies, public health authorities and H.M.O. executives--share a goal. The result: an outpouring of medical articles and studies on the subject and a cornucopia of new tactics, devices and programs all aiming to cajole patients to remember their pills.
People in general take about 75 percent of their medications as prescribed,` said Joyce Cramer, a medical researcher at Yale University and an authority on drug-taking behavior. But within that figure the range of misbehavior is wide. Nancy Houston Miller, a nurse who is the associate director of Stanford University's Cardiac Rehabilitation Program in Palo Alto, estimated that 10 to 20 percent of patients grossly flout medication regimens--never filling the prescriptions or taking only a few token pills. About 50 percent take doses more or less correctly. And an all-important 30 to 40 percent in the middle are `partial compliers,` forgetful enough that the medication may have only a fraction of its desired effect or may actually be harming them, but well-intentioned and able to be trained to do better.
Patients with serious diseases who are veterans at taking medication, cardiac-transplant patients, for instance--are usually better pill takers than those with silent conditions like high blood pressure, Dr. Urquhart said. But in general, predicting what patient will display which pill-taking behavior often yields surprises. Income, education, sophistication and competence in other parts of life correlate only very poorly with pill-taking behavior, the experts agree. People who know the purpose of the medication and the way it is supposed to work often do better than others. But education has its definite limits in inducing good pill-taking behavior: doctors, for example, are notoriously poor at it. In one large study of heart-attack prevention in male doctors in the 1980's, a full 30 percent of doctors were disqualified because they proved unable to take a single pill reliably every day.
Thus, as valuable as educational brochures, package inserts and videotapes may be, they are often now supplemented with a range of new compliance tools.
Some tools are million-dollar, labor-intensive programs. At Stanford, for instance, Ms. Miller has shown that heart-attack patients assigned to a nurse who spends hours educating them about diet, smoking, exercise and drug treatment, and then makes follow-up phone calls at home, are far more likely to stay on their medications than those who receive standard medical care.
Similarly, in New York City, a program in which city health department workers actually hand tuberculosis patients their medications every morning and watch them swallow has been credited with substantially increasing cure rates for the disease in the last five years.
Other new gadgets encourage patients to supervise themselves. A famous prototype for these devices was the circular container developed in the 1960's to help women remember their daily oral contraceptive pill. Flat blister-packs of prescription medications are now widely used in Europe to serve the same purpose, Dr. Urquhart said.
At the AIDS clinic at Yale-New Haven Hospital, every patient is supplied with a large rectangular pillbox whose 28 compartments can hold a week's worth of medications to be taken several times a day, said Dr. Gerald Friedland, a professor of medicine at Yale who directs the AIDS program. Current treatment for AIDS requires patients to take up to two dozen pills daily, often with different requirements for each, like an empty or a full stomach. `What's special about H.I.V. infection is the sheer complexity of the medications,` Dr. Friedland said. `One of the definite predictors of poor adherence to treatment is the complexity of the regimen.`
Other gadgets now on the market include simple electronic alarms that can be programmed to sound at intervals throughout the day, like the ALR tag made by TDI, and more sophisticated beepers that flash messages (`Time to take a gemfibrozil now,` one made by Medprompt might tell patients with heart disease) as well.
And the newest devices entering offices and clinics can actually provide patients with little monthly medication report-cards, for both patient and doctor to inspect and try to improve.
They are pill-bottle caps fitted with a battery and a computer chip that remembers every time the bottle cap is opened and closed. Once a month the chip's memory can be downloaded into a computer and turned into a graph of exactly when during the month the patient dipped into the vial." (see New York Times, Science Times, Jun. 2, 1998).
Hirsch et al. U.S. Pat. No. 5,084,482 discloses a novel method employing compositions containing as an active antioxidant or anti-inflammatory agent the amino acid methionine, and/or one or more related compounds.
This disclosure is based on the discovery that certain methionine or methionine-type companies in the dl-form or d-form at relatively high well-tolerated doses are potent antioxidant and anti-inflammatory agents in man and animals. The methionine compounds in high daily dosage thus may act in vivo to inhibit oxidative effects. All the preferred methods include at least one methionine compound.
Stamler U.S. Pat. No. 5,385,937 discloses administration of a nitrosating compound, such as nitroglycerin, nitric oxide etc. and related compounds for the treatment or prevention of disease states resulting from hyperhomocystinemia.
Valentine et al. U.S. Pat. No. 5,427,799 discloses sustained release composition and method utilizing xanthan gum and an active ingredient such as niacin or analgesic. Xanthan gum and an excipient promotes sustained release.
Kuhits U.S. Pat. No. 5,466,469 discloses a Granular Drug Delivery System utilizing a gel-forming dietary fiber and pharmaceutically active compound.
Fike U.S. Pat. No. 5,612,382 discloses a composition for percutaneous absorption of pharmaceutically active ingredients aspirin, vitamins, vasodilators, and/or analgesics in hydroxyalkyl amide as carrier for transdermal treatment of certain ailments.
Lockett U.S. Pat. No. 5,626,884 discloses a maintenance regime with controlled intake of particular vitamins, mineral and micronutrient formulations, drastically reducing the incidence and severity of sickle cell disease crisis.
Ismail U.S. Pat. No. 5,656,620 discloses treatment and prophylaxis of pain involving administration of vitamin E combined with salicylic acid in a pharmaceutically acceptable carrier or adjuvant.
Moshyedi U.S. Pat. No. 5,770,215 discloses a vitamin supplement containing in one tablet from 5% to 1000% of the RDA of vitamins and a therapeutically effective amount of vascular occlusion inhibiting compound which is preferably aspirin. The vitamins are selected from vitamins A, D, E, K, C, thiamin, riboflavin, niacin, niacinamide, B6, folate, B12, biotin, pantothenic acid and mixtures thereof. Herbal and mineral ingredients can also be present. The composition can be in one capsule or one tablet form.
Against this background there remains a need for improved formulations which can be effectively produced and taken, and improved presentation thereof for facilitated compliance with prescribed medication including such formulations, for preventing and limiting coronary heart disease, strokes, heart attacks and peripheral vascular disease.